p53-mediated control of aspartate-asparagine homeostasis dictates LKB1 activity and modulates cell survival

Longfei Deng, Pengbo Yao, Le Li, Fansen Ji, Shuang Zhao, Chang Xu, Xun Lan and Peng Jiang ()
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Longfei Deng: Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University
Pengbo Yao: Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University
Le Li: Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University
Fansen Ji: Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University
Shuang Zhao: Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University
Chang Xu: Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University
Xun Lan: Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University
Peng Jiang: Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Asparagine synthetase (ASNS) catalyses the ATP-dependent conversion of aspartate to asparagine. However, both the regulation and biological functions of asparagine in tumour cells remain largely unknown. Here, we report that p53 suppresses asparagine synthesis through the transcriptional downregulation of ASNS expression and disrupts asparagine-aspartate homeostasis, leading to lymphoma and colon tumour growth inhibition in vivo and in vitro. Moreover, the removal of asparagine from culture medium or the inhibition of ASNS impairs cell proliferation and induces p53/p21-dependent senescence and cell cycle arrest. Mechanistically, asparagine and aspartate regulate AMPK-mediated p53 activation by physically binding to LKB1 and oppositely modulating LKB1 activity. Thus, we found that p53 regulates asparagine metabolism and dictates cell survival by generating an auto-amplification loop via asparagine-aspartate-mediated LKB1-AMPK signalling. Our findings highlight a role for LKB1 in sensing asparagine and aspartate and connect asparagine metabolism to the cellular signalling transduction network that modulates cell survival.

Date: 2020
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DOI: 10.1038/s41467-020-15573-6

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